SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103)

Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC₅₀ values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21^WAF1/CIP1, and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.     

The highly conserved serine threonine kinase StkP of Streptococcus pneumoniae contributes to penicillin susceptibility independently from genes encoding penicillin-binding proteins

Background  

The serine/threonine kinase StkP of Streptococcus pneumoniae is a major virulence factor in the mouse model of infection. StkP is a modular protein with a N-terminal kinase domain a C-terminal PASTA domain carrying the signature of penicillin-binding protein (PBP) and prokaryotic serine threonine kinase. In laboratory cultures, one target of StkP is the phosphoglucosamine mutase GlmM involved in the first steps of peptidoglycan biosynthesis. In order to further elucidate the importance of StkP in S. pneumoniae, its role in resistance to β-lactams has been assessed by mutational analysis in laboratory cultures and its genetic conservation has been investigated in isolates from infected sites (virulent), asymptomatic carriers, susceptible and non-susceptible to β-lactams.     

Biomarkers in risk assessment of asbestos exposure

Developments in the field of molecular epidemiology and toxicology have given valuable tools for early detection of impending disease or toxic condition. Morbidity due to respiratory distress, which may be due to environmental and occupational exposure, has drawn attention of researchers worldwide. Among the occupational exposure to respiratory distress factors, fibers and particles have been found to be main culprits in causing diseases like asbestosis, pleural plaques, mesotheliomas and bronchogenic carcinomas. An early detection of the magnitude of exposure or its’ effect using molecular end points is of growing importance. The early inflammatory responses like release of the inflammatory cells collected by non-invasive methods give an indication of the unwanted exposure and susceptibility to further complications. Since free radicals like O₂⁻, OH, OOH, NO, NOO, etc. are involved in the progression of asbestos-related diseases and lead to cytogenetic changes, an evaluation of antioxidant states reducing equivalents like GSH and ROS generation can be a good biomarker. The cytogenetic end points like chromosomal aberration, micronucleus formation and sister chromatid exchange give indication of genetic damage, hence they are used as effective biomarkers. New techniques like fluorimetric analysis of DNA unwinding, alkaline elution test, fluorescent in situ hybridization and comet assay are powerful tools for early detection of initiation of disease process and may help in planning strategies for minimizing morbidity related to asbestos fiber exposure. The present review article covers in detail possible biomarkers for risk assessment of morbidity due to fibers/particles in exposed population.